PO.CL05.05 · 临床研究
Axl是cDC1中I型IFN的负性调控因子，阻碍抗肿瘤免疫
Axl is a negative regulator of type I IFN in cDC1s hindering anti-tumor immunity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：受体酪氨酸激酶Axl广泛参与肿瘤进展和免疫逃逸，但其在抗肿瘤免疫中的作用仍不明确。
方法：使用动物模型、遗传杂交、细胞实验以及来自人和小鼠肿瘤的单细胞RNAseq，研究Axl对肿瘤生长的作用。
结果：在此，我们揭示Axl是树突状细胞中I型干扰素信号的关键负性调控因子，并对CD8⁺ T细胞启动和肿瘤控制产生直接影响。Axl缺陷小鼠表现出延迟的肿瘤生长，这依赖于CD8⁺ T细胞和BATF3，凸显了对交叉提呈cDC1的需求。条件性敲除模型证实，仅在树突状细胞（而非巨噬细胞）中缺失Axl即足以通过I型干扰素通路增强抗肿瘤免疫。在机制上，Axl的消除增强了cDC1的交叉启动能力，并放大了STING激动剂和放疗的治疗效果。
结论：这些发现将Axl定位为cDC1中一个内在检查点，其限制干扰素驱动的免疫，揭示了树突状细胞的固有调控塑造适应性抗肿瘤应答的一种机制。
查看英文原文 English abstract
Background: The receptor tyrosine kinase Axl is widely implicated in tumor progression and immune evasion, yet its role in antitumor immunity remains poorly defined.
Methods: Investigate the role of Axl on tumor growth, using animal models, genetic crosses, cellular assays, and single cell RNAseq from human and mouse tumors.
Results: Here, we uncover Axl as a key negative regulator of type I interferon signaling in dendritic cells, with direct consequences for CD8⁺ T cell priming and tumor control. Axl-deficient mice exhibited delayed tumor growth that was dependent on CD8⁺ T cells and BATF3, highlighting a requirement for cross-presenting cDC1s. Conditional knockout models confirmed that Axl loss in dendritic cells-but not macrophages-was sufficient to enhance antitumor immunity through type I interferon pathways. Mechanistically, Axl ablation increased cDC1 cross-priming capacity and amplified the therapeutic effects of a STING agonist and radiotherapy.
Conclusion: These findings position Axl as an intrinsic checkpoint in cDC1s that restrains interferon-driven immunity, revealing a mechanism by which innate regulation of dendritic cells shapes adaptive antitumor responses.
利益披露 Disclosure
I. Gonzalez, None.
E. A. Elghonaimy,
ALPA Biosciences Stock.
Q. Zhang, None..
I. Montgomery, None..
P. Q. Leung, None..
A. P. Rodriguez, None..
R. A. Brekken, None.
T. A. Aguilera,
Novocure Other, Advisory Board.
Renovo Rx Travel.
Avelas Biosciences Stock.
ALPA Biosciences g., Board of Directors, non-salaried role).